Figure 3.

A functional crosstalk between cardiac cells, affecting by cardiotoxic drugs. (a) In response to physiological stress, endothelial cells secrete survival factors, NRG1. NRG1 acts on HER2/HER4 in cardiomyocytes, inducing survival pathways, blocking ROS production, and favoring NO release. Cardiac fibroblasts produce components of extracellular matrix to ensure appropriate heart architecture also in response to changes in cardiac homeostasis. (b)The defensive mechanism mediated by NRG1 does not occur in presence of trastuzumab. Moreover, the oxidative stress induced by anticancer drugs, such as DOX or trastuzumab, induces activation of NFκB in the endothelium, with an expression of proinflammatory cytokines, IL-2 and IL-6, activating immune cells. The activated immune cells promote a profibrotic phenotype of fibroblasts, with abnormal deposition of extracellular matrix and pathological cardiac remodeling.